Structural mapping of GABRB3 variants ...
Document type :
Article dans une revue scientifique: Article original
PMID :
Permalink :
Title :
Structural mapping of GABRB3 variants reveals genotype-phenotype correlations
Author(s) :
Johannesen, K. M. [Auteur]
University of Southern Denmark [SDU]
Iqbal, S. [Auteur]
Guazzi, M. [Auteur]
Mohammadi, N. A. [Auteur]
Perez-Palma, E. [Auteur]
Schaefer, E. [Auteur]
De Saint Martin, A. [Auteur]
Abiwarde, M. T. [Auteur]
Mctague, A. [Auteur]
Pons, R. [Auteur]
Piton, A. [Auteur]
Kurian, M. A. [Auteur]
Ambegaonkar, G. [Auteur]
Firth, H. [Auteur]
Sanchis-Juan, A. [Auteur]
Deprez, M. [Auteur]
Jansen, K. [Auteur]
De Waele, L. [Auteur]
Briltra, E. H. [Auteur]
Verbeek, N. E. [Auteur]
Van Kempen, M. [Auteur]
Fazeli, W. [Auteur]
Striano, P. [Auteur]
Zara, F. [Auteur]
Visser, G. [Auteur]
Braakman, H. M. H. [Auteur]
Haeusler, M. [Auteur]
Elbracht, M. [Auteur]
Vaher, U. [Auteur]
Smol, Thomas [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Lemke, J. R. [Auteur]
Platzer, K. [Auteur]
Kennedy, J. [Auteur]
Klein, K. M. [Auteur]
Au, P. Y. B. [Auteur]
Smyth, K. [Auteur]
Kaplan, J. [Auteur]
Thomas, M. [Auteur]
Dewenter, M. K. [Auteur]
Dinopoulos, A. [Auteur]
Campbell, A. J. [Auteur]
Lal, D. [Auteur]
Lederer, D. [Auteur]
Liao, V. W. Y. [Auteur]
Ahring, P. K. [Auteur]
Moller, R. S. [Auteur]
Gardella, E. [Auteur]
University of Southern Denmark [SDU]
University of Southern Denmark [SDU]
Iqbal, S. [Auteur]
Guazzi, M. [Auteur]
Mohammadi, N. A. [Auteur]
Perez-Palma, E. [Auteur]
Schaefer, E. [Auteur]
De Saint Martin, A. [Auteur]
Abiwarde, M. T. [Auteur]
Mctague, A. [Auteur]
Pons, R. [Auteur]
Piton, A. [Auteur]
Kurian, M. A. [Auteur]
Ambegaonkar, G. [Auteur]
Firth, H. [Auteur]
Sanchis-Juan, A. [Auteur]
Deprez, M. [Auteur]
Jansen, K. [Auteur]
De Waele, L. [Auteur]
Briltra, E. H. [Auteur]
Verbeek, N. E. [Auteur]
Van Kempen, M. [Auteur]
Fazeli, W. [Auteur]
Striano, P. [Auteur]
Zara, F. [Auteur]
Visser, G. [Auteur]
Braakman, H. M. H. [Auteur]
Haeusler, M. [Auteur]
Elbracht, M. [Auteur]
Vaher, U. [Auteur]
Smol, Thomas [Auteur]

Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Lemke, J. R. [Auteur]
Platzer, K. [Auteur]
Kennedy, J. [Auteur]
Klein, K. M. [Auteur]
Au, P. Y. B. [Auteur]
Smyth, K. [Auteur]
Kaplan, J. [Auteur]
Thomas, M. [Auteur]
Dewenter, M. K. [Auteur]
Dinopoulos, A. [Auteur]
Campbell, A. J. [Auteur]
Lal, D. [Auteur]
Lederer, D. [Auteur]
Liao, V. W. Y. [Auteur]
Ahring, P. K. [Auteur]
Moller, R. S. [Auteur]
Gardella, E. [Auteur]
University of Southern Denmark [SDU]
Journal title :
Genetics in Medicine
Abbreviated title :
Genet. Med.
Volume number :
24
Pages :
681-693
Publication date :
2023-09-06
ISSN :
1098-3600
English keyword(s) :
Epilepsy
GABA
GABRB3
Genetics
Mapping
GABA
GABRB3
Genetics
Mapping
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
Purpose
Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability ...
Show more >Purpose Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype–phenotype correlations. Methods Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated. Results We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain. Conclusion These genotype–phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.Show less >
Show more >Purpose Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype–phenotype correlations. Methods Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated. Results We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain. Conclusion These genotype–phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
Université de Lille
CHU Lille
CHU Lille
Collections :
Submission date :
2024-05-15T22:09:01Z
2024-06-19T10:25:24Z
2024-06-19T10:25:24Z